An adequate gas exchange and a sufficient supply of 02 to tissues depends on the patency of the airways which are regulated by central and peripheral nervous systems. The Howard University response to this RFA is based on the need for fundamental research in regard to central and peripheral nervous control of breathing and airway functions; including olfaction. Disturbances in neuronal regulatory mechanisms, as a consequences of alterations in sensory and/or motor innervations at different levels of organization, may cause serious health problems. To address some of these issues, we propose four interrelated projects. Project 1 will define central determinants of breathing and airway instability during behavioral changes by examining how CNS sites that regulate rapid eye movements (REM) and quiet (non-REM sleep might exert a differential control on respiratory related skeletal and airway smooth muscles. project 2 will study the neurochemical profile of the central chemoreceptor neurons, their receptor types, as well as their neuronal projections to respiratory and airway related motoneurons. Project 3 will investigate gene regulation involved in plasticity of the olfactory system as well as signaling during the acute phase response to physical, chemical and biological stressors. Project 4 will investigate the role of sensory innervation of the airway and gene regulatory mechanisms triggered by environmental agents, which operate in a feed forward manner enhancing airway inflammation and bronchoconstriction, and alterations in the signaling system linked to airway hyper-reactivity, airway narrowing and refractoriness to airway dilating influences. New investigative approaches will be used in these studies to answer questions which will enhance our understanding of the fundamental mechanisms underlying regulation of respiratory and airway functions. Furthermore, assembling a team of multi-disciplinary scientists from outside of the Howard University research community will enable us to generate new information that will advance knowledge, and ask relevant questions regarding future studies. This proposal is an expression of the commitments made by the College of Medicine, investing in infrastructure and guaranteeing long-term support, to bring talented researchers to work together. The university is committed to provide appropriate release time for the participants in this program to perform the research described herein.